Accumulation of myeloid-derived suppressor cells (MDSC) in tumor-bearing hosts is an important mechanism of suppression of T and NK cell responses and a major obstacle to immunotherapy. MDSC inhibitory activity has been attributed to several pathways, including the depletion of the amino acids arginine and cysteine; the release of reactive oxygen species, peroxynitrites, and prostaglandin E2; and the induction of regulatory T cells. Unfortunately, the understanding of the immune-inhibitory mechanisms induced by MDSC has not yet been translated into successful therapies to globally block MDSC function in cancer. We postulate that the identification and inhibition of the central mediators of MDSC-immune regulatory activity in tumors will overcome T cell suppression and increase the efficacy of T cell-based immunotherapies. In this proposal, we aim to determine the role of the C/EBP homologous stress-related protein (Chop), a common stress sensor usually associated with the induction of cellular apoptosis, as a master regulator of the immune suppressive activity of MDSC. We hypothesize that the induction of Chop in MDSC by multiple stress-related factors, globally drives the ability of MDSC to inhibit T cell responses and modulates MDSC turnover/survival homeostasis. Therefore, therapeutic inhibition of Chop or its upstream mediators in tumors will block MDSC function, restore protective anti-tumor effector T cell responses, and increase the efficacy of T cell-based immunotherapies. This hypothesis is based upon our extensive preliminary findings suggesting the central role of Chop on MDSC activity. We will test our hypothesis and achieve the objectives of this study through the following Specific Aims: (1) To determine the mechanisms by which the expression of Chop in the stroma regulates the immune suppression activity and the accumulation of MDSC in tumors. (2) To determine the mechanisms that induce Chop expression in tumor-infiltrating MDSC. (3) To test the prediction that pharmacological inhibition or genetic deletion of Chop will block MDSC function and increase the efficacy of T cell-based immunotherapies in cancer. Completion of the proposed study will describe for the first time how multiple stress factors in tumors drive global MDSC activity through a unique pathway. In addition, the results will help characterize and develop a novel therapeutic approach, which carries the potential to block the global immune inhibitory functions of MDSC and to restore protective T cell immunity in cancer. Moreover, the methodology established in this proposal could be applied into other diseases where MDSC are major mediators of T cell suppression.